The rapid conversion of the i to the I phenotype on postnatal red blood cells (RBCs) reflects the elaborate functions of cell surface branched-chain I antigenic structure. The adult i phenotype has been noted to be partially associated with congenital cataracts. These phenomena make the molecular genetics of the blood group I system and the regulation mechanism for I antigen expression in postnatal RBCs intriguing. It has been demonstrated that the human I locus expresses three IGnT forms, designated IGnTA, IGnTB, and IGnTC, which have different exon 1, but identical exons 2 and 3, coding regions. The uncommon molecular genetics of the I locus offers a new perspective of the formation and expression of the I antigen in different cells, and provides an insight into the questions derived from investigation of the adult i phenotype. The results obtained from molecular analysis of two adult i groups, with and without congenital cataracts, support the proposed molecular mechanism for the partial association of the two traits, namely that mutations that lead to the production of mutant IGnTC only, may result in an adult i phenotype but not congenital cataracts, whereas mutation events that occur in the common exon 2 or exon 3 regions, which result in the elimination of the activity of all three IGnT enzymes, would seem to lead to the development of both traits. This suggests that an I-gene defect may lead directly to the development of congenital cataracts. However, the result of the gene knock-out mouse model does not confirm this suggestion.
Analysis of the regulation for I antigen expression shows that i-to-I phenotypic transition during erythroid differentiation is regulated by the transcription factor CCAAT/enhancer binding protein α (C/EBPα), which enhances transcription of the IGnTC gene, consequently leading to the formation of the cell surface I antigen. Subsequent investigation further showed that phosphorylation of the Ser-21 residue on C/EBPα blocks C/EBPα activity on IGnTC gene induction, while dephosphorylation of C/EBPα Ser-21 occurs in both the granulopoietic and erythropoietic processes, leading to stimulation of IGnTC gene expression and consequently I antigen formation. These results demonstrate that the formation of I antigen during the development of erythrocytes, and also granulocytes, is determined by a mechanism that is known to be crucial to determining granulopoiesis, namely involvement of the transcription factor C/EBPα and Ser-21 dephosphorylation of this protein.